We report a mutation of UBE2A/HR6A, which encodes a ubiquitin-conjugating enzyme (E2), a member of the ubiquitin proteasome pathway, as the cause of a novel X-linked mental retardation (XLMR) syndrome that affects three males in a two-generation family. A single-nucleotide substitution, c.382C-->T in UBE2A, led to a premature UAG stop codon (Q128X). As a consequence, the predicted polypeptide lacks the 25 C-terminal amino acid residues. The importance of this terminal sequence for UBE2 function is inferred by its conservation in vertebrates and in Drosophila. UBE2A mutations do not appear to significantly contribute to XLMR, since no UBE2A mutations were identified in 15 families with nonsyndromic and 4 families with syndromic idiopathic XLMR previously mapped to intervals encompassing this gene. This is the first description of a mutation in a ubiquitin-conjugating enzyme gene as the cause of a human disease.
The prevalence of intellectual disability is around 3%; however, the etiology of the disease remains unclear in most cases. We identified a series of patients with X-linked intellectual disability presenting mutations in the Rad6a (Ube2a) gene, which encodes for an E2 ubiquitin-conjugating enzyme. Drosophila deficient for dRad6 display defective synaptic function as a consequence of mitochondrial failure. Similarly, mouse mRad6a (Ube2a) knockout and patient-derived hRad6a (Ube2a) mutant cells show defective mitochondria. Using in vitro and in vivo ubiquitination assays, we show that RAD6A acts as an E2 ubiquitin-conjugating enzyme that, in combination with an E3 ubiquitin ligase such as Parkin, ubiquitinates mitochondrial proteins to facilitate the clearance of dysfunctional mitochondria in cells. Hence, we identify RAD6A as a regulator of Parkin-dependent mitophagy and establish a critical role for RAD6A in maintaining neuronal function.
BackgroundThe gene YCL047C, which has been renamed promoter of filamentation gene (POF1), has recently been described as a cell component involved in yeast filamentous growth. The objective of this work is to understand the molecular and biological function of this gene.ResultsHere, we report that the protein encoded by the POF1 gene, Pof1p, is an ATPase that may be part of the Saccharomyces cerevisiae protein quality control pathway. According to the results, Δpof1 cells showed increased sensitivity to hydrogen peroxide, tert-butyl hydroperoxide, heat shock and protein unfolding agents, such as dithiothreitol and tunicamycin. Besides, the overexpression of POF1 suppressed the sensitivity of Δpct1, a strain that lacks a gene that encodes a phosphocholine cytidylyltransferase, to heat shock. In vitro analysis showed, however, that the purified Pof1p enzyme had no cytidylyltransferase activity but does have ATPase activity, with catalytic efficiency comparable to other ATPases involved in endoplasmic reticulum-associated degradation of proteins (ERAD). Supporting these findings, co-immunoprecipitation experiments showed a physical interaction between Pof1p and Ubc7p (an ubiquitin conjugating enzyme) in vivo.ConclusionsTaken together, the results strongly suggest that the biological function of Pof1p is related to the regulation of protein degradation.
We describe two different novel mutations in the PAX3 gene, detected in two families with cases of Waardenburg syndrome type I (WSI). The missense mutation detected in one family involved a single substitution in exon 2 (c.142 G > T) and was present both in the affected individual and in his clinically normal father. The mutation found in the second family consisted of a deletion of 13 bases, c.764-776del(TTACCCTGACATT), in exon 5.
Essa atividade prática é resultado de nosso trabalho de acompanhamento no Serviço de Aconselhamento Genético do Instituto de Biociências da Universidade de São Paulo e foi desenvolvida com a finalidade de ajudar no esclarecimento das dúvidas dos casais de primos cuja maior preocupação é o risco de virem a ter crianças afetadas em sua prole.
Por meio de um modelo didático simples, que utiliza caixas e palitos de fósforos, será possível entender o que ocorre com o gene envolvido na síndrome do cromossomo X frágil, a principal causa de deficiência mental herdada. A demonstração utiliza materiais simples, pode ser facilmente repetida e aborda conceitos genéticos como transcrição gênica e herança ligada ao cromossomo X. Para facilitar a compreensão da atividade, um material em vídeo também foi preparado (acesso ao vídeo: http://www.youtube.com/watch?v=bBxpOHrEOJ0). A idéia fundamental desse trabalho é que professores e pesquisadores possam utilizá-lo, respectivamente, com alunos e familiares de indivíduos com SXF (Síndrome do X Frágil), POF (Falência Ovariana Prematura, na sigla em inglês) e/ou FXTAS (Síndrome de Tremor e Ataxia associada ao X Frágil, na sigla em inglês). Pretendemos ainda que o maior número possível de pessoas tome conhecimento sobre esses quadros clínicos, permitindo um pequeno contato com o universo da pesquisa científica.
A atividade “O mapa da mina: entendendo o mapeamento gênico” é um recurso didático que possibilita a simulação da investigação científica sobre o funcionamento celular de um gene e sua identificação. Através da representação de um condomínio de casas e de seus moradores, faz-se uma associação com a célula eucarionte considerando-se algumas situações. Supõese que os moradores são funcionários de uma mesma empresa que procuram manter o equilíbrio e o bom funcionamento da fábrica. Assim, por analogia, durante o desenvolvimento da atividade, o professor pode propor diferentes situações atribuladas que interferem no bom funcionamento da célula, tentando torná-la semelhante à atividade de um cientista da área de genética humana, que busca identificar diversos tipos de genes e suas funções específicas.
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